The epidemic of obesity is a significant risk factor in five of the six most common forms of cancer, including pancreatic ductal adenocarcinoma (PDAC). Inflammatory responses associated with obesity lead to the dysregulation of adipose secreted cytokines, known as adipokines. In obese individuals, serum levels of leptin, a pro-tumorigenic adipokine, dramatically increase while the anti-tumorigenic adiponectin levels decrease, ultimately promoting cancer progression. Our efforts have shown that obesity induces adipocytes to increase leptin and IL-6 secretion, which exert pro-tumorigenic effects in PDAC cells that drive proliferation, migration and in vivo tumor growth. We have now identified that the anti- tumorigenic adipokine, adiponectin, counteracts the effects of pro-tumorigenic adipokines in obesity associated PDAC progression through multiple mechanisms. First, adiponectin antagonizes leptin and IL-6 induced activation of STAT3 and ERK signaling in PDAC cells resulting in suppression of PDAC growth. Second, adiponectin blocks activation of the Src homology region 2 containing protein tyrosine phosphatase (SHP-2), a key mediator of leptin and IL-6-induced RAF- RAS-ERK signaling. Third, adiponectin effectively inhibits adipokine-induced secretion of inflammatory cell attractants from tumor cells. Our results validate that adiponectin is a critical negative regulator of obesity associated PDAC progression and provide a novel therapeutic strategy for the treatment of PDAC. The goal of this proposal is to determine whether counteracting adipose secreted cytokines can inhibit PDAC progression. Our central hypothesis is that adiponectin overcomes innate resistance of PDAC by antagonizing adipokine mediated RAS activity through suppression of SHP-2 and by blocking inflammatory cell recruitment into the tumor microenvironment. The overall objective is to determine whether adiponectin represents a viable therapeutic strategy to counteract obesity driven PDAC. This will be accomplished by the following specific aims: Aim 1. Determine the anti- tumorigenic effects of adiponectin in obese-induced PDAC progression. In this aim, we will determine whether loss of adiponectin potentiates PDAC progression and whether adiponectin supplementation can counteract the pro-tumorigenic mechanisms of obesity. Aim 2. Determine the direct effect of SHP-2 inhibition on KRAS activation in obesity driven PDAC development and progression. This aim will determine whether loss or inhibition of the tyrosine phosphatase SHP-2 is sufficient to suppress obesity dependent PDAC progression. Aim 3. Determine if adiponectin regulation of ENA-78 mediates changes in the inflammatory immune microenvironment. This aim will investigate whether adiponectin can block adipokine mediated secretion of inflammatory chemoattractants from PDAC cells. The outcome of these specific aims will yield significant new knowledge regarding the mechanisms governing obesity dependent cancer risk and progression. Further, these studies will uncover potential therapeutic uses for adiponectin receptor agonists in PDAC.